Approximately 48,330 new cases of oropharyngeal cancer and 9,570 deaths will occur in the US during 2016. Despite vigilant monitoring and well-recognized risk factors for tumor recurrence over 1/3 of patients previously treated for oral squamous cell carcinoma (OSCC) develop life-threatening and often fatal recurrent cancers. Recent cancer-targeted therapies, which were developed to exploit cancers' reliance on overexpressed pathways and hopefully reduce collateral damage to healthy tissues, were thought to have cancer preventing potential. Their efficacies, however, become limited by cancer's alternate signaling pathways and compensatory mechanisms. OSCC is an extremely complex and consistently changing disease. Consequently, we hypothesize that OSCC secondary chemoprevention needs to be equally dynamic to disrupt its tumorigenic properties at multiple levels. We have identified three complementary agents [fenretinide (4-HPR), 2-methoxyestradiol (2-ME) & tocilizumab (TOC)] which are capable of multifaceted chemoprevention at the intracellular, tumor-stroma, and tumor-ECM levels when locally delivered. While these agents have been used as monotherapy, they have not been combined as chemopreventives, much less in controlled release delivery formulations. The Specific Aims of this proposal are: 1) Investigate the effect of 4-HPR, 2-ME and TOC on OSCC gratuitous signaling, intracrine/paracrine growth loops, unlimited replication, and conversion to an invasive phenotype., 2) Optimize controlled-release local delivery formulations for secondary OSCC chemoprevention., 3) Evaluate the efficacy and pharmacokinetics of locally delivered 4-HPR, 2-ME and TOC using an orthotopic OSCC xenograft model. Research methodology will include a variety of biochemical, molecular and computational analyses (Aim 1), pharmaceutical chemistry technology (Aim 2), and tumor biology-pathology and pharmacokinetics studies (Aim 3). Anticipated results include: 1) all 3 agents will suppress inappropriately sustained proliferation, 2) TOC's IL-6R antagonism will suppress IL-6 mediated intracrine/paracrine signaling and IL-6's Stat3 activation, 3) 4-HPR and 2-ME will induce apoptosis with additive effects when in combination, 4) 4-HPR will induce keratinocyte differentiation, 5) 4-HPR and 2-ME will have the greatest signaling inhibition in cells with constitutive Stat3 and NF-?B activation, 6) 4-HPR `s abilities to bind and block ATP binding on the FAK & Pyk2 signaling kinases and inhibit F-actin organization and 2- ME's perturbation of microtubules will suppress invasion. It is also anticipated that agent combinations will provide more extensive chemopreventive responses and that optimal cancer-preventing effects will be observed during use of 3 agents concurrently both in vitro and in vivo.